The candidate has a long-standing interest in understanding the role of sex steroid hormones in normal physiology and pathophysiology. He has gained a strong interest in understanding how aging impacts this influence, and he is currently pursuing a career in the field of aging. He has a strong background in estrogen action, but is currently under training to study aging and age-related diseases. The goal of this grant is to substantially strengthen the candidate's research expertise and extend the candidate's scientific network in the field of aging, allowing the candidate to create his own niche in researc on aging. The candidate's long-term goal is to bridge the gap between the tissue-specific biology of estrogen signaling and the aging-associated biology of mitochondrial damage-driven senescence, with the intent of discovering new pathways as potential targets for clinical diagnosis, prevention, and/or treatment of aging and age-related diseases. ENVIRONMENT: The Buck Institute for Research on Aging is the best place to develop the candidate's expertise in age research. The candidate will be mentored by Judith Campisi, who is a leading expert in cellular senescence and aging, and co-mentorship of Simon Melov, who is a leading expert in using mouse models to study mitochondrial dysfunction and aging. His advisory committee will include (a) Martin Brand, one of the foremost authorities on mitochondrial bioenergetics, (b) Chris Benz, who is expert in estrogen receptor signaling, (c) Ervin H. Epstein, Jr., who is a well-renowned dermatologist and an expert in non-melanoma skin cancers (basal cell carcinomas), and (d) Pierre-Yves Desprez, an excellent successful faculty, expert in breast cancer biology. The candidate will have access to and will be trained through the state-of-the-art core facilities at the Buck Institute: (a) Bioenergetics, Morphology and Imaging Core for mitochondrial bioenergetics and imaging, (b) the Genomics Core for gene expression studies, and (c) the Animal Core for skin function assessment. He will also attend a formal course in aging (the National Institute of Aging Summer Training Course in Experimental Aging Research), a course in bioenergetics, and annual scientific meetings. He will also participate in research seminars, journal clubs, and career training seminars offered at the institute. RESEARCH: Accumulation of mitochondrial oxidative damage is thought to be one of the key mechanisms driving the aging process and can contribute to skin aging. Because estrogen can regulate mitochondrial function in several cell types, this study proposes that mitochondria play an important role in estrogen action in the skin during aging. On one hand, estrogen protects the skin from accumulating mitochondrial oxidative damage and mitochondria-driven senescence. While on the other hand, excessive mitochondrial oxidative damage during aging can lead to cellular senescence and eventually influence estrogen signaling, creating a milieu reminiscent of aged skin. This study will (a) test if excessive mitochondrial oxidative damage can lead to phenotypic defects (i.e. cellular senescence) in mammalian skin epidermis by using a transgenic mouse model deficient in superoxide dismutase 2 (sod2); (b) address the molecular mechanism of estrogen in preventing mitochondrial oxidative damage; (c) investigate the mechanism of cellular senescence in influencing estrogen action in mammalian cells; and (d) test the physiological impact of estrogen action during the aging process in skin by using an ovariectomy mouse model. This proposal can help explain the beneficial effects of estrogen on skin, and potentially identify the mitochondrion as an important organelle for estrogen action during the aging process of skin. PUBLIC HEALTH RELEVANCE: Estrogen prevents signs of skin aging, including improved wound healing and increased skin integrity, but it can also increase risk for various diseases, such as breast and endometrial cancer, and coronary heart disease. Hence, distinguishing the signal transduction pathways involved in the beneficial and detrimental effects of estrogen is important for developing drug interventions that will selectively slow down skin aging with only minimal side effects caused by estrogen. This proposal aims to identify the involvement of mitochondria, particularly mitochondrial oxidative damage, on estrogen action in the aging process of skin.